Graham M A, Newell D R, Foster B J, Calvert A H
Drug Development Section, Institute of Cancer Research, Surrey, U.K.
Cancer Chemother Pharmacol. 1989;23(1):8-14. doi: 10.1007/BF00258450.
CI-941 is a new synthetic DNA-binding agent selected for phase I clinical evaluation. The drug has broad-spectrum antitumour activity against a number of murine tumours and, in contrast to doxorubicin, is unlikely to induce cardiotoxicity by a free-radical-mediated mechanism. In this study the toxicity and pharmacokinetics of CI-941 were studied in the mouse to enable the implementation of a pharmacokinetically guided dose-escalation strategy in patients. Following a single i.v. bolus injection in mice, CI-941 induced dose-dependent leukopenia. The white blood cell counts were suppressed on day 3 by 18%, 50% and 65% of control, at doses of 10, 15 and 20 mg/kg CI-941, respectively. Other toxicities such as weight loss, alopecia, diarrhoea and convulsions were observed at doses greater than 20 mg/kg. Lethality studies in female Balb-c mice resulted in an LD10 value of 20 mg/kg (95% confidence limits; range, 19-21 mg/kg) and an LD50 value of 22 mg/kg (95% confidence limits; range, 21-23 mg/kg). The pharmacokinetics of CI-941 were studied at four dose levels from 1/10 of the LD10 to the LD10 (20 mg/kg). The drug was rapidly cleared from the plasma (250-400 ml/min per kg) at a rate approaching the cardiac output of mice, displaying triphasic plasma pharmacokinetics. The area under the plasma CI-941 concentration vs time curve (AUC) was linear with respect to the dose, up to and including 15 mg/kg (AUC = 110 microM x min at 15 mg/kg), but became non-linear at 20 mg/kg (AUC = 277 microM x min). Despite 80%-84% plasma protein binding, CI-941 was rapidly and extensively distributed into tissues, especially the kidney. Following i.v. bolus injections at doses of 1.5 and 15 mg/kg, elimination of the parent compound by urinary excretion accounted for 12%-18% of the delivered dose. A phase-I starting dose (based on that equivalent to 1/10 of the LD10 in the mouse) of 5 mg/m2 CI-941 is recommended for single administration schedules. In addition, a pharmacokinetically guided dose-escalation strategy, based on achieving a target AUC of 110 microM x min, is proposed.
CI-941是一种被选用于I期临床评估的新型合成DNA结合剂。该药物对多种小鼠肿瘤具有广谱抗肿瘤活性，并且与阿霉素不同，不太可能通过自由基介导的机制诱发心脏毒性。在本研究中，对CI-941在小鼠体内的毒性和药代动力学进行了研究，以便在患者中实施药代动力学指导的剂量递增策略。在小鼠单次静脉推注后，CI-941诱导了剂量依赖性白细胞减少。在第3天，当CI-941剂量分别为10、15和20mg/kg时，白细胞计数分别被抑制至对照的18%、50%和65%。在剂量大于20mg/kg时，观察到其他毒性，如体重减轻、脱发、腹泻和惊厥。对雌性Balb-c小鼠的致死性研究得出LD10值为20mg/kg（95%置信限；范围为19 - 21mg/kg），LD50值为22mg/kg（95%置信限；范围为21 - 23mg/kg）。在从LD10的1/10到LD10（20mg/kg）的四个剂量水平上研究了CI-941的药代动力学。该药物从血浆中快速清除（每千克250 - 400ml/min），清除速率接近小鼠的心输出量，呈现三相血浆药代动力学。血浆CI-941浓度-时间曲线下面积（AUC）在剂量达到并包括15mg/kg时与剂量呈线性关系（15mg/kg时AUC = 110μM×min），但在20mg/kg时变为非线性（AUC = 277μM×min）。尽管CI-941有80% - 84%与血浆蛋白结合，但它能快速且广泛地分布到组织中，尤其是肾脏。在1.5和15mg/kg剂量静脉推注后，母体化合物经尿液排泄的消除量占给药剂量的12% - 18%。对于单次给药方案，建议CI-941的I期起始剂量为5mg/m²（基于相当于小鼠LD10的1/10）。此外，还提出了一种基于达到110μM×min目标AUC的药代动力学指导的剂量递增策略。
